Combined Risk Factors Induce T Cell‐Mediated Diastolic Dysfunction in a Novel Mouse Model of Heart Failure with Preserved Ejection Fraction (HFpEF)

Abstract

Heart Failure with Preserved Ejection Fraction (HFpEF) is a prevalent and heterogenous cardiovascular syndrome characterized by impaired cardiac relaxation (diastolic function) with preserved contractility (systolic function), generally as a result of the presentation of several comorbidities. Despite its high and increasing prevalence, there are no therapies available to directly treat or cure HFpEF. Obesity and hypertension, the two dominant risk factors of HFpEF, have been independently associated with T cell inflammation, however, the inflammatory mechanisms driving HFpEF by these two comorbidities together, and T cell contributions, remain elusive. We hypothesized that T cell immune responses and cardiotropism promote diastolic dysfunction and HFpEF. C57/BL6 (wild-type, WT) and T cell receptor alpha-deficient (Tcra-/-) male mice were fed a high fat diet (HFD) with L-NAME-treated water (0.5 g/L) for 5 weeks to mimic obesity and hypertension, respectively, a recently established model of HFpEF. Age- and sex-matched mice were fed standard chow (STD) as controls. Cardiac function was assessed using hemodynamic analyses, and plasma was collected to evaluate systemic levels of pro- and anti-inflammatory cytokines. The heart, mediastinal lymph nodes, inguinal lymph nodes, and spleen were harvested to characterize cardiac and systemic immune cell populations by flow cytometry. Cardiac tissue was also collected for gene expression analysis by qPCR of markers of adverse cardiac remodeling and HFpEF. WT mice fed HFD/L-NAME had increased cardiac CD11b+ cell abundance and increased CD4+ T cell infiltration compared to controls. Furthermore, in contrast to control mice, HFD/L-NAME-treated mice had an increased abundance of CD44hi/CD62Llo effector T cells in the mediastinal lymph nodes and spleen. This was associated with increased passive chamber stiffness (end-diastolic pressure volume relationship, EDPVR) and decreased expression of the unfolded protein response (UPR) proteins spliced form of X-box binding protein 1 and binding immunoglobulin protein (XBP1s and BIP), hallmarks of HFpEF. Additionally, HFD/L-NAME induced a 2.5-fold increase in plasma levels of IL-17, without altering the levels of interferon-gamma or IL-2. Strikingly, Tcra-/- mice did not develop diastolic dysfunction when fed HFD/L-NAME, supporting a causal role of T cells in HFpEF pathology. We conclude that T cell activation and recruitment to the heart contribute to diastolic dysfunction in HFpEF. Further studies will interrogate the mechanisms by which combined risk factors prime T cells for cardiac infiltration and effector function in the heart to induce and drive HFpEF.